Myelodysplasia

The myelodysplastic syndromes (MDS) are a collection of disorders that predominately affect older patients with the median age of 63 at diagnosis. MDS is a heterogenous group of disorders characterized by abnormal growth of the myeloid bone marrow components. This section examines the common mechanism believed to underlie the MDS and then relates that to the propensity of these conditions to evolve into acute leukemia. In addition, we discuss the classification, natural history, and treatment options for MDS.

Pathogenesis
The pathogenesis of MDS is complicated. Current theory holds that MDS results from chromosomal injury that occurs in stepwise progression. Beginning with an initial predisposition to genomic instability, progressive insults result in chromosomal damage that culminates in MDS and can further progress to AML. Common chromosomal alterations involve 5, 7, 8, and 20. The involved chromosome areas are usually rich in hematopoietic genes. In addition to gross chromosome alterations, submicroscopic DNA mutations result in abnormal oncogene expression. Because of secondary DNA damage, exposure to chemicals or prior chemotherapy increases the risk for developing MDS. Although these genes may play a pathologic role in the development of MDS, we still do not understand the critical molecular events that lead to these diseases. The progression of MDS to leukemia is likely the result of additional genetic mutations that provide the evolving clone further growth advantages.

The biology of the disease is further complicated by other abnormalities, including aberrant cytokine production and responsiveness, altered stem cell adhesion, abnormal marrow microenvironment, early cell death secondary to accelerated apoptosis, and immunomediated marrow suppression. With all these contributing factors, MDS is ultimately a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and peripheral cytopenias.

Classification The WHO classification system was recently proposed to replace the previous FAB classification system. Some of the subsets are listed here. The distinction among these groups is based on the appearance of the bone marrow. The clinical presentation, however, can be very similar. Low blood counts (cytopenias) are the hallmark, and anemia occurs in the majority of patients. Isolated neutropenia or thrombocytopenia also occurs, but the usual picture is trilineage cytopenias. On examination of the peripheral blood, abnormal morphology is usually apparent. The findings in the marrow are more obvious, with hypercellularity, bizarre nuclear morphology, abnormal iron granules (sideroblasts), and nuclear/cytoplasmic maturation dysynchrony evident. All lines are affected, although frequently one lineage is more markedly dysplastic. An important determinant of overall prognosis is the percentage of blast cells in the bone marrow.